Process for the preparation of nornicotine



Patented Jan. 18, 1949 r 2,459,696 r a i a I PaocEssFoRTHEa ARAH I F NoRmcoT 7 Ball] G, Haines and A bner Eisner, Philadelphia,

and Charles F. Woodward, Abington, Pa assignorsto the United States of America'as represented ,-by .the Secretary of Agriculture No Drawing. Application July 12, 194.4,

-S.erial'No.544,6 1 8 j 5 Claims. (organ-42511) (Granted-under the act of March 3, 11883, as

amended April '30, 1928;

This application is made under the Act 0f March 3, 1883, as amended by the Act of April 30, 1928, and the invention herein described, if patented, maybe manufactured and used by or for the Government of the "United States of America for governmentalpurposes Without the payment to us of any royalty thereon.

This invention relates to the preparation of nornicotine, and vmore particularly toa process for the production of nornicotine by the reaction of myosmine with hydrogen. n n

The alkaloid, nornicotine, occurs naturally as the laevo (1-) enantiomorph in "various tobacco types and the highest concentrations of this nitrogenous base are often found intobaccos containing'small quantities of nicotine. Thenatural occurrence of the optical antipode, di-nornicotine, has been established by its isolation from Duboz'sia Hopwoodz'z'.

In addition to these natural sources, several laboratory methods have been developed .for the preparation of nornicotine. Most of these procedures have utilized nicotine ,as a starting material and the demethylation to nornicotine has been accomplished in either a direct or a stepwise manner. The oxidation of nicotine with potassium permanganate or silver oxide has produced low yields of nornicotine. The reaction of acetic anhydride or benzoic anhydride with nicotine oxide has been reported .to yield nornicotine. The demethylation of nicotine to nornicotine has also been accomplished by the reaction of nicotine with bezoic or dihydrocinnamic acids at high temperatures. Nornicotine has also been obtained by the hydrolysis of 1 (3- pyridyl) 1 amino -4- ethoxybutane with concentrated hydrobromic acid.

We have 'found that nornicotine may be prepared in good yields by a new process involving the reaction of myosmine with hydrogen. The reduction of myosmine to nornicotine is accomplished by reacting a solution of myosmine with hydrogen in the-presence of a catalytic agent. Preferred catalystsforxthereductioniare platinum oxide and palladium oxide or mixtures of these materials.

The reduction of myosmine to nornicotine can be carried out in aqueousor in acetic acid solutions. Although the solvent has some eifect on the yield of nornicotine it appears that this is duelargely to the reflect of the solvent on the hydrogen ion concentration of the solution. ,Al-

though nornicotine is obtainable over a wide pH range we prefer .to carry out the reduction at about pH 6.0 to 9.0. I

Since ,nornicotine is more basic than myosmine the ".pH of the reaction mixture gradually increases .during' the conversion of myosmine to nornicotine. Highest yields of nornicotine are obtained when buffers are employed tomai'ntain the pHofjt-he solution within a relatively narrow range, ,Eor example,a buffer mixture consisting Of one part I sodium hydrogen phosphate .dodecahydrate is effective in .maintaining an aqueous solution of myosmine at about pI-I 6.0-9.0 during almost complete reduction to :nornicotine. On-the other h and,-an appreciable decrease in the nornicotine yield may be observed when provisions are not made for control of .the hydrogen .ion. concentration. Furthermore,sidereactionsoccur, yiveld ing undesirable resinous products, when efiective buffering agents are not included in the aqueous reaction mixture or whenthereduction iscarried out in glacial acetic acid. I

A convenient laboratory procedure for the reduction of myosmine to nornicotineinvolves shaking of the reaction mixture at room temperature under an init-ial hydrogen pressureof about fifty pounds "per square inch. The reaction is discontinued when approximately the theoretical quantity of hydrogen has been taken up. In some experiments an excess to be advantageous, j Nornicotine maybe isolatedfrom' the reaction mixture by several "procedures." Steam distillation may be employed to separate the [steam volatile products from the non-steam-volatile nornicotine. When appreciable quantities of non-steam-volatile by products are obtained in the initial reduction it is advantageous to separate nornicotlne from these impurities by chroof citric .acid and two parts of di of hydrogen may be'found v 3 matographic adsorption of the nornicotine on activated alumina. However, when the best conditions for the reduction of myosmine to nornicotine are employed only negligible quantities of undesirable products are formed and it is not necessary to employ either steam distillation or chromatographic adsorption steps in the isolation procedure.

The following isolation method was found to be efiicient and adequate in the absence of appreciable quantities of reaction by-products: The reaction mixture is made stronglyv alkaline, extracted with etherjand-the ether solution then extracted with dilute hydrochloric acid. The acid solution is concentrated on a steam bath and then added to a saturated aqueous solution of picric acid. Precipitation of the insoluble alkaloid picrate is essentially complete after several hours. The precipitate is filtered and then recrystallized from water. In a typical example, thisrecrystal lized picrate melted at about 192-193. C- and was identified as nornicotine picrate by a mixed melta ing point with an authentic sample. Nornicotine was isolated from the picrate by treating the latextracting the alter with an alkaline solution, kaloid with ether, and fractionally distilling the ether extract.

:,-iractionating column.

from the steam distillation residue by preclpitaa A mixture consisting distilled water, 1.0 g. citric acid monohydrate, and "2.0g. jdisodium hydrogen phosphate dodecahyauthentic specimen of nornicotine picrate b the method of mixed melting points.

Example 3 tion of the insoluble picric acid derivative. The

identity of this derivative was established as in Example 1.

Example 4 of 2.0 g. myosmine, 45 g.

drate was adjusted to pH 6.2 by the addition of 'aqueous sodium hydroxide solution. One-tenth The following examples will further illustrate the nature of our invention:

, Example 1 l A mixtureconsisting' of 5 g. myosmine, 73.5 g. glacial acetic acid, and 0.2 g. -platinum oxide was placed in a pressure bottle connected to a hydrogen cylinder. The hydrogen pressure was, increased to 50 pounds per square inch and the bottle was then shaken at room temperature until 0.0765 mole of hydrogen had reacted. More than twice the theoretical amount of hydrogen was allowed to react yields of nornicotine were thus obtained than when smaller quantitiesoi hydrogen wereutilized underthese' experimental conditions. The reactionmixture was made strongly alkaline, extracted with ether, and ,the ether solution then extracted with hydrochloricjacid. The acid extract wasadded to an aqueous picric acid solution to precipitate nornicotine picrate. After treat ment with norite'and'recrystallization from water the alkoloid. picrate melted By, the method of mixed melting points this prod uct was shown to be identical with an authentic sample of nornicotine picrate.

By similar procedures nornicotine picrate was obtained when palladium oxide was employed asa catalyst instead of platinum oxide; A mixed platinum oxide-:ceric sulfate catalyst was'also effective under these conditions.

Example 2 Glacial acetic acid was. added to a solution consisting of 1 g. myosmine, 4.1 g. sodiumacetate trihyd-rate, and 50 g. water .until the solution was at about pH 6.0. The catalyst, consisting of 0.045 g. platinum oxide and 0.021 g. palladium oxide was then added and the resulting mixturewas reacted with hydrogen as. in -lilxample 1 until 0.0124 moles of gas were absorbed. Upon discontinuation of the hydrogenation it was observed that the reaction mixture-had increased to pH 8.5. The catalyst was then filtered oil and the filtrate added to an aqueous picric acid solution. Theprecipitated alkaloid picrate was filtered and since it was found that higher I at about 192-194 0.

"of agram of platinum oxide was added and the vmix ure was then reacted with hydrogen as in Example 1 until 0.014 mole hydrogen were absorbed .Aftercompletion of the reduction the reaction mixture was at pH 8.9. The reaction mixture was made strongly alkaline, extracted with ether, and the ether. solution then extracted with dilute hydrochloric "acid. The acid extract was concentrated on a steam bath and then added to an aqueous picric. acid solution. The precipitated alkaloid picratefwas filtered and recrystalliz'edirom hotv water. This purified derivative melted at 192.2-192.8? C. and was shown to be identical with an'authenticsample of nornicotine picrate by the method of mixed melting points.

Under these reaction conditions the quantity of hydrogen absorbed was in excellent agreement with the theoretical amount. The reaction proceeded smoothly with the formation of none of the resinous by-products observed in Examples 1,

- 2, and 3. I'.The yield obtained under these conditions was about 85 per cent which was appreciably higher than the yields obtained in Examples 1-3 inclusive.

Having thus described our invention, we claim: 1. A process for themanufacture of nornicotine comprising reacting with hydrogen a solution of myosmine bufiered with a mixture of acetic acid and. sodium acetate to maintain-the solution at a fied picrate was shown'to be identicalwith an pH in. the range 6 to 9, and recovering the nornicotine. a

2. A process for the manufacture of nornicotine comprising'reacting[with hydrogen a solution of myosmine buffered with'a mixture of acetic acid and sodium acetate in the presence of a catalyst chosen from the group consisting of platinum 6O oxide and palladium oxide and recovering the nornicotine. 3. ,A process for manufacture of nornicotine in w'hichthe starting material is 'rnyosmine, comprisingreacting the myosmine with hydrogen in the presence of a 'oatalystchosen from the group consisting of platinum oxide, palladium oxide, and a mixture of platinum oxide andpalladium oxide, buffering the reaction mixture during the reduc tion to nornicotine to maintain it at pH 6 to 9, and recovering the nornicotine from the reaction mixture.

The processdefined by claim 3 wherein the myosmine solution is maintained within the range disodium' hydrogen "phosphate.

5-. The process defined by claim 3 wherein the myosmine solution is main tained within the range of pH 6.0 to 9.0 by the ad REFERENCES CITED dition of acetic acid and fil'ghzf fallligwggferll'ieterences are of record in the sodium acetate.

5 Spath, et aL, Berichte 713, pp. 100-106 (1938). PAUL G. HAINES. Berichte, vol. 71, 1276-1281 (1938). ABNER EISNER. Richter-Textbook of Organic Chemistry, pp. CHARLES F. WOODWARD. 272-273, John Wiley and Sons, New York, N. Y.

Hodgeman et a1, Handbook of Physics 8: Chemisb y, DP. 312-313, 28 edition, (1944). 

